This invention relates to a process for the preparation of optically active 6-hydroxymethyl-4-(tert-butyldimethylsilyloxy)-(4R,6S)-tetrahydro-2H-2-pyranone (xcex2-hydroxy-xcex4-lactone) having formula 1. 
More particularly it relates to a process for the preparation of the said compound using Cis,cis-3,5-di(methylcarbonyloxy)cyclohexylacetate having formula 2 
The compound xcex2-hydroxy-xcex4-lactone (1) is an important intermediate in the synthesis of biologically active drugs e.g. compactin, atorvastatin, fluvastatin, cholesterol lowering drugs.
Hitherto known processes for the synthesis of xcex2-hydroxy-xcex4-lactone (1) involves
a) Addition of lithium enolate of ethylacetate to (S)-2,2-dimethyl-1,3-dioxlane-4-ethanol, which in derived from L-malic acid, followed by acid treatment. (T. Rosen, M. J. Taschner and C. H. Heathcock, J. Org. Chem., 1984, 49, 3994-4003)
b) Multistep chemical manipulation of tri-acetyl-D-glucal (T. Rosen, M. J. Taschner, C. H. Heathcock, J. Org. Chem., 1984, 49, 3994; F. G. Kathawala, Mountain Lake N. J. USP 4739,073)
c) Coupling of (S)-2,2-dimethyl-1,3-dioxalane-4-ethanal with optically active (R)-methyl-p-tolylsulphoxide which in turn obtained by oxidation of methyl-p-tolysulphide with baker yeast, followed by desulphurization and few chemical manipulation (J. Beecher, I. Brackerridge, S. M. Roberts, J. Tang and A. J. Willetts, J. Chem. Soc. Perkin Tran.I 1995, 1641; Tetrahedron 1995, 51, 13217)
d) Deprotection and hydrolysis of 6-cyanomethyl-2,2-dimethyl-1,3-dioxane-4-acetate, which in turn obtained by two carbon homologation on optically active ethyl-3-hydroxy-4-cyanobutyrate and followed by stereoselective reduction (P. L. Brower, D. E. Butler, C. F. Deering, T. V. Le, A. Millar, T. N. Nanninga and B. D. Roth, Tet. Lett, 1992, 33, 2279-82
e) Racemic and optically active xcex2-hydroxy-xcex4-lactone from cis-cyclohexane-1,3,5-triol (K. Prasad and O. Repic, Tet. Lett., 1984, 25, 2435-38; H. Suemune, M. Takahashi, S. Maeda, Z. Fxi and K. Sakai, Tet. Asymm. 1990, 1, 425-8, M. Canda, V. Eyken and M. Vandewalle, Tet. Asymmetry 1990, 1, 17-20).
f) Enzymatic kinetic resolution of racemic xcex2-hydroxy-xcex4-lactone by transesterification with vinyl acetate in THF using Chromobacteriun viscosum lipase as catalyst at 40xc2x0 C. [Crosby, J. B.; Andrew, J. H.; John, A. L. WO 9306235 A1 CA 119:936292 (1993)]
g) Chemoenzymatic route involving kinetic resolution through lactone formation in ether catalyzed by PPL [Bonini, C.; Pucci, P.; Viggiani, L. J. Org. Chem. 1991, 56, 4050]
h) Chemoenzymatic route involing enzymatic desymmetrization of intermediate diacetate, followed by chemical conversions. [Bonni, C.; Racioppi, R.; Righi, G.; Viggiani, L. J. Org. Chem. 1991, 58, 802]
i) Chemoenzymatic synthesis starting from endohydroxylacto which is obtained by enzymatic resolution [MaCague, R.; Olivo, H. F.; Roberts, S. M. Tetrahedron Lett. 1993, 34, 3785]
j) Diastereoselective synthesis of lactone based on Eu(fod)3 catalyzed highly diastereoselective [4+2] cycloaddition of 1-methoxybuta-1,3-diene to (2R)-N-glyoxyloxyborane-10,2-sultam and further chemical transformations [Bauer, T.; Kozak, J.; Chauis, C.; Jurczak, J. J. Chem. Soc.; Chem. Commun. 1990, 1178 and Tetrahedron: Asymmetry 1996, 7, 1391]
k) Chiral synthesi using (R)-O-benzylglycidol as starting material [Takano, S.; Shimazaki, Y.; Sekiguchi, Y.; Ogasawara, K. Synthesis 1989, 539]
l) Asymmetric synthesis based on Red-Al promoted intramolecular reductive cleavage of Benzyl 4-hydroxy-2-butenyl ether structures. [Hatakeyama, S.; Satoh, K.; Takano, S. Tetrahedron Lett. 1993, 34, 7425]
The prior art processes have following drawbacks:
1. The processes use chemicals such as butyl lithium, lithium aluminum hydride, methoxy-diethylborane which are costly and difficult to handle and therefore make the process difficult.
2. All known process are however involves large number of synthetic steps resulting in low over all yields.
The main object of the present invention is to provide a new process for the preparation of xcex2-hydroxy-xcex4-lactone (1), which obviates the drawbacks of the prior art processes and use cheaper and easily accessible chemicals.
Another object of the present invention is to provide (i) selective Baeyer-Villiger rearrangement of 3-hydroxy-5-t-butyldimethylsilyloxy-1-cyclohexanone (9) with chemical reagent or Baeyer Villiger oxidase and (ii) enantioselective hydrolysis of cis-3-(methylcarbonyloxy)-5-(tert-butyldimethylsilyloxy)cyclohexylacetate with enzyme.
Accordingly the present invention provides a process for the preparation of xcex2-hydroxy-xcex4-lactone of formula 1 using novel intermediates which comprises
a) reacting a compound of formula 2 with a lipase enzyme in a buffer having 
xe2x80x83pH ranging between 5 to 7, at a temperature ranging from 25 to 30xc2x0 C. for a period ranging between 19 to 30 hrs. extracting the reaction mixture with an organic solvent, removing the solvent by evaporation to obtain cis,cis-3-hydroxy-5-methylcarbonyloxy-cyclohexylacetate having formula (3), 
b) reacting a compound of formula 3 with tert-butyldimethylsilylchloride in an organic solvent in the presence of an organic base at a temperature ranging from xe2x88x9215 to 20xc2x0 C. for a period ranging from 6 to 12 hrs, separating the organic solvent, to obtain cis,cis-3-(methylcarbonyloxy)-5-(tert.butyldimethylsilyloxy)cyclohexylacetate having formula 4, 
c) reacting a compound 4 with a lipase enzyme in a buffer having pH in the range of 5 to 8, at a temperature ranging from 25 to 30xc2x0 C. for a period ranging between 24 to 60 hrs., extracting the mixture with an organic solvent, removing the solvent by evaporation and on column chromatography to obtain 3-hydroxy-5-(tert.butyldimethylsilyloxy)-(1S,3R,5R)-cyclohexylace-tate having formula 5, 
d) reacting a compound of formula 5 with dihydropyran in an organic solvent in the presence of p-toluene sulphonic acid at a temperature ranging from 5 to 10xc2x0 C. for a period ranging from 2 to 5 hrs, quenching the above reaction with an aqueous sodium bicarbonate, separating the organic layer, drying, on evaporating and column chromatography to obtain 3-tetrahydro-2H-2-pyranyloxy-5-(tert.butyldimethylsilyloxy)-(1S,3R,5R)-cyclohexylacetate having formula 6, 
e) reacting a compound of formula 6 with an anhydrous potassium carbonate in methanol at room temperature for a period ranging from 2 to 6 hrs, evaporating the solvent, extracting with an organic solvent, washing with brine solution, drying, evaporating and column chromatography to obtain 3-tetrahydro-2H-2-pyranyloxy-5-(tert.butyldimethylsilyloxy)-(1S,3R,5R)-cyclohexan-1-ol having formula 7, 
f) reacting a compound of formula 7 with pyridinium chlorochromate in an organic solvent at room temperature for a period ranging from 6 to 8 hours, extracting the above mixture with an ether, washing with brine, drying, on evaporating and column chromatography to obtain 3-tetrahydro-2H-2-pyranyloxy-5-(tert.butyldimethylsilyloxy)-(1S,3R,5R)-cyclohexan-1-one having formula 8, 
g) reacting a compound of formula 8 with magnesium bromide in an organic solvent at a temperature ranging from 5 to 30xc2x0 C. for a period ranging from 1 to 12 hours, quenching the above reaction ammonium chloride, separating the organic layer, drying and on evaporating to obtain 3-hydroxy-5-(tert-butyldimethyl silyloxy)-(3S,5R)-cyclohexan-1-one having formula 9, 
h) reacting a compound of formula 9 with m-chloroperbenzoic acid at room temperature for a period ranging from 16-24 hours, extracting the compound with an orgainc layer, washing with sodium metabisulphite, brine, drying and on evaporation to obtain 6-hydroxymethyl-4-(tert-butyldimethylsilyloxy)-(4R,6S)-tetrahydro-2H-2-pyranone having formula 1. 
In an embodiment of the present invention the organic solvent used in steps a, c, e and h for the extraction of the product is selected from the group consisting of ethyl acetate, chloroform, dichloromethane and t-butanol.
In an another embodiment of the present invention the organic solvent used in steps b, e, f and g for the reaction is selected from the group consisting of ethyl acetate, chloroform, dichloromethane, methanol and diethyl ether.
In yet another embodiment of the present invention the organic base used in step b for the reaction is selected from triethylamine and pyridine.
In yet another embodiment of the present invention the buffer used in steps a and c for the reaction is selected from phosphate buffer and citrate buffer.
In still another embodiment of the present invention the lipase used in steps a and c for the reaction is selected from the group consisting of pig procain lipase (PPL), pig liver esterase (PLE) and chicken liver acetone powder (CLAP).
In yet another embodiment the present invention provides a compound cis,cis-3-hydroxy-5-methylcarbonyloxy-cyclohexylacetate having formula (3), 
In yet another embodiment the present invention provides a compound cis,cis-3-(methylcarbonyloxy)-5-tert.butyldimethylsilyloxy)cyclohexylacetate having formula 4, 
In yet another embodiment the present invention provides a compound 3-hydroxy-5-(tert.butyldimethylsilyloxy)-(1S,3R,5R)-cyclohexylacetate having formula 5, 
In yet another embodiment the present invention provides a compound 3-tetrahydro-2H-2-pyranyloxy-5-(tert.butyldimethylsilyloxy)-(1S,3R,5R)-cyclohexylacetate having formula 6, 
In yet another embodiment the present invention provides a compound 3-tetrahydro-2H-2-pyranyloxy-5-(tert.butyl dimethylsilyloxy)-(1S,3R,5R)cyclohexan-1-ol having formula 7, 
In yet another embodiment the present invention provides a compound 3-tetrahydro-2H-2-pyranyloxy-5-(tert.butyldimethylsilyloxy)-(1S,3R,5R)-cyclohexan-1-one having formula 8, 
In yet another embodiment the present invention provides a compound 3-hydroxy-5-(tert-butyldimethylsilyloxy)-(3S,5R)-cyclohexan-1-one having formula 9, 
Cis,cis-3,5-di(methylcarbonyloxy)cyclohexylacetate (2) is prepared by treatment of acetic anhydride with cis-1,3,5-cyclohexantriol which is made by known literature procedure (Strong, P. N.; Keana, J. F. W. J Org. Chem. 1975, 40, 956).